Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have addressed the capacity of HIV-1 infection to alter the growth of primary CD4+ T cells, but at the clonal level. Single T cells were expanded in the presence of PHA, IL-2, and small numbers of accessory dendritic cells. We report two new findings. First, T cells from seropositive individuals, even those with AIDS and markedly reduced CD4+ counts, exhibit a normal cloning efficiency, and proliferative capacity. This result is in contrast to two prior reports of a low cloning efficiency in CD4+ T cells from HIV-1-infected patients. Second, when we added high doses of exogenous HIV-1 to T cell clones from control subjects, we observed infection but not cytotoxicity or loss of CD4+ cells, following addition of virus stocks at days 0, 3, and/or 7 of clonal growth. The same HIV-1 isolates markedly reduced CD4+ T cells in bulk mononuclear cultures. When tested at day 11, HIV-1 mRNA was expressed in some cells of exogenously infected clones by in situ hybridization; when tested at day 18, several clones could transactivate a TAT-sensitive cell line. These findings suggest that the loss of CD4+ T cells in infected individuals is not the inevitable result of the activation of latent infection, or spread of a productive infection, during clonal growth.
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PMID:Most CD4+ T cells from human immunodeficiency virus-1 infected patients can undergo prolonged clonal expansion. 257 7

Human immunodeficiency virus (HIV) envelope glycoprotein is synthesized as a polyprotein precursor of 160 kDa (gp 160) and is subsequently cleaved into an amino terminus subunit, gp 120, and a carboxyl terminus transmembrane subunit, gp 41. Two synthetic peptides corresponding to amino acid sequences 735-752 and 846-860, respectively, as deduced from the nucleotide sequence of HTLV-IIIB gp 160 were synthesized and used to assess their effects on normal human lymphocyte blastogenesis. Peptides 735-752 and 846-860 conjugated to protein carriers, but not free peptides, exerted a pronounced suppression of the normal human lymphocyte proliferative response to concanavalin A (Con A), phytohemagglutinin (PHA), pokeweed mitogen (PWM), and alloantigens. A synthetic peptide homologous to a 17 amino acid sequence of the gene product of HIV trans-acting transcriptional (TAT III) gene had no suppressive effects. Peptides 735-752 and 846-860 also inhibited the IL-2-dependent proliferation of the murine CTLL-2 cell line and the PHA-induced proliferation of normal mouse spleen cells. HIV peptide-induced suppression of human blastogenesis required a 2- to 3-day incubation of responder cells with peptides, suggesting that binding of peptides to the cell membrane was not sufficient for suppression. These results suggest that, in addition to the selective cytopathic effects of HIV, the etiological agent of the acquired immunodeficiency syndrome (AIDS), on the T-helper/inducer lymphocyte subset, viral peptide-mediated immunosuppression may also play an important role in the pathogenesis of the disease. Moreover, these data clearly indicate the need to address the potential immunosuppressive property of HIV antigens in the effort to select and develop effective prophylactic means against AIDS.
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PMID:Synthetic peptides homologous to HIV transmembrane glycoprotein suppress normal human lymphocyte blastogenic response. 325 17

The trans-activator of transcription or TAT gene from HIV-1 encodes a protein that increases the processivity of transcription from the HIV-1 genome. TAT protein can also affect cellular processes in the absence of its ribonucleic HIV target sequence trans activation response element and may be responsible for some aspects of HIV pathogenesis apart from infectious virus or other viral gene products. We have previously shown that TAT72 decreases CTL activity in TAT72-transgenic mice, and we now demonstrate aberrant regulation of mitogen-elicited IL-2 at both transcriptional and translational levels. In contrast, alloantigen stimulation resulted in increased IL-6 and IL-10 production in the TAT72-transgenic mice. Con A-stimulated cultures of splenic lymphocytes from TAT72-transgenic mice do not undergo clonal proliferation of CD4+ cells as compared with CD8+ cells monitored over 72 h. These results suggest that TAT is sufficient to induce some pathology associated with AIDS and is a potent immunologic manipulator apart from its function as trans-activator.
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PMID:Aberrant regulation of cytokines in HIV-1 TAT72-transgenic mice. 862 96

Although JNK is a potential target for treating chronic inflammatory diseases, its role in T lymphocyte function remains controversial. To overcome some of the previous limitations in addressing this issue we have used the recently described transactivator of transcription-JNK-interacting protein (TAT-JIP) peptide, a specific inhibitor that was derived from the minimal JNK-binding region of the scaffold protein, JNK-interacting protein 1 (JIP-1), coupled to the short cell-permeable HIV TAT sequence. Pretreatment of purified human T lymphocytes with the TAT-JIP peptide inhibited the phosphorylation of endogenous jun activated by PHA-PMA. This was associated with a corresponding inhibition of lymphoproliferation, and of IL-2, IFN-gamma, lymphotoxin, and IL-10 cytokine production. Similar results were also found using mouse splenic T cells. Examination of the specificity of TAT-JIP revealed that although the peptide was more selective than the pharmacological inhibitor, SP600125, it also inhibited cyclin-dependent kinase 2, p70 ribosomal protein S6 kinase, and serum and glucocorticoid-regulated kinase activity. Nevertheless, these data demonstrate for the first time the ability of the TAT-JIP peptide to inhibit the JNK pathway and the phosphorylation of jun in intact cells, thereby preventing the activation of the transcription factor, AP-1, and the production of Th1 and Th2 cytokines. Thus JNK could potentially be a target for the development of drugs for the treatment of autoimmune inflammatory diseases.
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PMID:The effect of the JNK inhibitor, JIP peptide, on human T lymphocyte proliferation and cytokine production. 1898 Nov 52